Researchers report that low-oxygen conditions increase hypoxia-inducible-factor (HIF-1), which worsens chronic kidney disease (CKD).
The study was conducted using mice that had been engineered to turn off expression of HIF-1-alpha, a critical subunit of HIF-1, in their kidneys. One kidney from each mouse was put under oxygen stress by obstructing the ureter, and the other kidney served as a control. As long as HIF-1-alpha was silenced, fibrosis was reduced in the oxygen-deprived kidney.
“We found that HIF-1 is more stable when oxygen is in short supply and that HIF-1 causes kidney epithelial cells to regress to a less-differentiated cell type,” states lead author Volker Haase, M.D., assistant professor of medicine, renal electrolyte and hypertension division, University of Pennsylvania School of Medicine. “This transition is driven by HIF-1 turning on many genes that promote the synthesis of fibrous connective tissue, thus interfering with the kidney’s normal filtering function.”
The investigators also examined kidney biopsies from patients with diabetes who also suffer from CKD for HIF-1a levels. Normal kidneys had almost no HIF-1-alpha, whereas kidneys from diabetics had moderate to high expression of HIF-1-alpha.
The research was conducted by scientists at University of Pennsylvania School of Medicine, Nara Medical University, Friedrich-Alexander University, University of California, San Diego, University of Michigan Medical School, and University of Munich. The findings appear in a December issue of the Journal of Clinical Investigation.